There are various electroporation applicators and methods of use known in the art. The prior art methods involve two independent procedures, the introduction of a target molecule into a target tissue and the subsequent electroporation of the target tissue to induce electroporation. The majority of prior art methods require two separate devices, one to introduce the target molecule and a second to provide for the electroporation of the target tissue site.
Prior art methods to introduce a target molecule into a target tissue include the use of intrusive instruments or the application of an electric field using devices that must directly contact the skin with the stated purpose of altering the skin to allow a drug to move through the external skin barrier.
The delivery of molecules by electroporation in vivo is typically, but not necessarily, carried out by first exposing the cells (located within a tissue) of interest to the molecule to be delivered. This is accomplished by placing the molecules of interest into the extracellular space by injection, jet injection, transdermal delivery, infusion into tissue or blood vessel, or other means known in the art. The cells are then exposed to electric fields by administering one or more direct current pulses. Pulsed electric fields are normally applied using an electrical generator and electrodes that contact or penetrate a region of tissue, which allows electrical energy to be transmitted to the cells of interest. Electrical treatment is typically, but not necessarily, conducted in a manner that results in a temporary cell membrane destabilization with minimal cytotoxicity.
The intensity of electrical treatment is described by the magnitude of the applied electric field. This field is defined as the voltage applied to the electrodes divided by the distance between the electrodes. Generally, electric field strengths ranging from 100 to 5000V/cm have been used; this range has been dictated by the need to interfere with the cell membrane to effect the uptake of the molecular species desired. In addition, the field strength required for delivery is also a function of the type of tissue to be treated, with some requiring higher fields owing to their specific natures.
High field strengths, 100V/cm and greater, were used exclusively in the past. The duration of the applied fields is also an important factor, and the relationship between field strength and duration is critical. The current state of the art utilizes high electric field strengths to effect the membrane change and requires pulse durations that are very brief in order to achieve molecular delivery. The concept of very long pulse durations (greater than 100 ms) has heretofore never been used with respect to the field strength, enabling in vivo molecular delivery using almost insignificant electric fields. In fact, the converse was held to be true by practitioners of the art; operating parameters with short-duration high fields being held as the only way to achieve electroporation. The pulsed electric fields used for molecule delivery are generally rectangular in shape; however, exponentially decaying pulses and bipolar pulses have also been used. Molecular loading has been performed with pulse widths ranging from microseconds to milliseconds. The number of pulses delivered typically has ranged from one to eight, with multiple pulses being applied during the course of a treatment.
Accordingly, there is a need in the art for a method and apparatus to facilitate the directed delivery and subsequent electroporation of a target molecule in-vivo without the associated pain, muscle contraction, and cell damage associated with direct-contact electroporation applicators.